The β-(Phosphatoxy)alkyl Radical Rearrangement ... - ACS Publications

Constants, Arrhenius Parameters, and Structure Activity ... The Arrhenius equation describing the migration of the β-phenyl-β-(diphenylphosphatoxy)e...
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J. Am. Chem. Soc. 1996, 118, 6666-6670

The β-(Phosphatoxy)alkyl Radical Rearrangement. Rate Constants, Arrhenius Parameters, and Structure Activity Relationships David Crich* and Xian-Yun Jiao Contribution from the Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street, Rm. 4500, Chicago, Illinois 60607-7061 ReceiVed April 18, 1996X

Abstract: Rate constants for the migration of a series of p,p-disubstituted β-(diarylphosphatoxy)alkyl migrations have been determined in benzene at reflux by competition against the benzeneselenol clock reaction. There is a strong linear correlation of log(k) with the Hammett σp but not with various σ• parameters indicating that the migration occurs through a highly polarized transition state resembling an alkene radical cation loosely bound to a phosphate anion. The Arrhenius equation describing the migration of the β-phenyl-β-(diphenylphosphatoxy)ethyl radical in toluene was found to be log(kR) ) (10.2 ( 0.8) - (7.0 ( 1.0)/2.3RT.

Introduction β-(Phosphatoxy)alkyl radicals are implicated in the degradation of oligonucleotides by free radicals, including various antitumor antibiotics and hydroxyl radicals.1 Exploration of the fundamental chemistry of this clearly important class of radicals with simple model systems has uncovered a previously unknown radical migration, the β-(phosphatoxy)alkyl rearrangement (1 f 2).2,3 A series of stereochemically and deuterium labeled

Figure 1. 5-Center-5-electron TS.

Figure 2. 3-Center-3-electron TS.

probes revealed this rearrangement to proceed in benzene solution in a non-dissociative manner through two parallel, competing transition states representing formal 1,2- and 2,3X Abstract published in AdVance ACS Abstracts, July 1, 1996. (1) See: (a) Stubbe, J.; Kozarich, J. W. Chem. ReV., 1987, 87, 1107. (b) Hecht, S. M. Acc. Chem. Res., 1986, 19, 383. (c) Hecht, S. M. Bioconjugate Chem. 1994, 5, 513. (d) Christner, D. F.; Frank, B. L.; Kozarich, J. W.; Stubbe, J.; Golik, J.; Doyle, T. W.; Rosenberg, I. E.; Krishnam, B. J. Am. Chem. Soc. 1992, 114, 8763. (e) Haggeland, J. J.; De Voss, J. J.; Heath, J. A.; Townsend, C. A. J. Am. Chem. Soc. 1992, 114, 9200. (f) Kappen, L. S.; Goldberg, I. H.; Frank, B. L.; Worth, L.; Christner, D. F.; Kozarich, J. W.; Stubbe, J. Biochemistry 1991, 30, 2034. (g) Goldberg, I. H. Acc. Chem. Res. 1991, 24, 191. (h) Nicolaou, K. C.; Dai, W.-M. Angew. Chem., Int. Ed. Engl. 1991, 30, 1387. (i) Nicolaou, K. C.; Smith, A. L. Acc. Chem. Res. 1992, 25, 497. (j) Lee, M. D.; Ellestad, G. A.; Borders, D. B. Acc. Chem. Res. 1991, 24, 235. (k) Dedon, P. C.; Goldberg, I. H. Chem. Res. Toxicol. 1992, 5, 311. (l) von Sonntag, C. In The Chemical Basis of Radiation Biology; Taylor and Francis: London, 1987. (m) SchulteFrohlinde, D.; Hildenbrand, K. In Free Radicals in Synthesis and Biology; Minisci, F., Ed.; Kluwer, Dordrecht, 1989; p 335. (n) von Sonntag, C.; Schuchmann H-P. Angew. Chem., Int. Ed. Engl. 1991, 30, 1229. (o) Dizardoglu, M. In DNA and Free Radicals; Halliwell, B., Aruoma, O. I., Eds.; Ellis Horwood: Chichester, 1993; p 19. (p) von Sonntag, C.; Hagen, U.; Scho¨n-Bopp, A.; Schulte-Frohlinde, D In AdVances in Radiation Biology; Lett, J. T., Adler, H., Eds.; Academic: New York, 1981; Vol. 9, p 110. (q) Giese, B.; Beyrich-Graf, X.; Erdmann, P.; Petretta, M.; Schwitter, U. Chem. Biol. 1995, 2, 367. (r) Breen, A. P.; Murphy, J. A. Free Radicals Biol. Med. 1995, 18, 1033. (2) (a) Crich, D.; Yao, Q.; Filzen, G. F. J. Am. Chem. Soc. 1995, 117, 11455. (b) Crich, D.; Yao, Q. J. Am. Chem. Soc. 1994, 116, 2631. (c) Crich, D.; Yao, Q. Tetrahedron Lett. 1993, 34, 5677. (d) Crich, D.; Yao, Q. J. Am. Chem. Soc. 1993, 115, 1165. (3) (a) Koch, A.; Giese, B. HelV. Chim. Acta 1993, 76, 1687. (b) Koch, A.; Lamberth, C.; Wettrich, F.; Giese, B. J. Org. Chem. 1993, 58, 1083.

shifts [Figures 1 and 2, X ) P(OR)2], and to be in certain cases highly or even completely stereoselective.2 Initially, Giese3 and we2 had predicted the existence of the β-(phosphatoxy)alkyl migration on the grounds of its probable relationship to the intriguing β-(acyloxy)alkyl, or Surzur/Tanner rearrangement.4 Subsequently, we have shown this class of radical ester rearrangements to be somewhat general and to include the migration of nitrates and sulfonates,5 and even the contraction and/or expansion of lactones.6 We have postulated that each of these rearrangements occurs in apolar, aprotic solvents through the two parallel mechanisms of Figures 1 and 2 [X ) P(OR)2, CR, NO, S(O)R] with the distribution a factor of the particular system.2a The polarized nature of the 5-center-5electron transition state for the β-(acyloxy)alkyl migration (Figure 1, X ) CR) was first put forward by Beckwith and Ingold on the grounds that the rearrangement was accelerated by polar solvents and was more rapid for trifluoroacetates than for simple acetates.7 Consideration of the structures of the (4) (a) Surzur, J.-M.; Teisser, P. C. R. Acad. Sci. Fr. Ser. C 1967, 264, 1981. (b) Surzur, J.-M.; Teisser, P. Bull. Soc. Chim. Fr. 1970, 3060. (c) Tanner, D. D.; Law, F. C. J. Am. Chem. Soc. 1969, 91, 7537. (d) Beckwith, A. L. J.; Duggan, P. J. J. Chem. Soc., Perkin Trans. 2 1993, 1673 and footnote 2a and references therein cited. (5) (a) Crich, D.; Filzen, G. F. Tetrahedron Lett. 1993, 34, 3225. (b) Crich, D.; Filzen, G. F. J. Org. Chem. 1995, 60, 4834. (6) (a) Crich, D.; Beckwith, A. L. J.; Filzen, G. F.; Longmore, R. Submitted for publication. (b) Furber, M.; Kraft-Klaunzer, P.; Mander, L. N.; Pour, M.; Yamaguchi, T.; Murofushi, N.; Yamane, H.; Schraudolf, H. Aust. J. Chem. 1995, 48, 427. (7) (a) Barclay, L. R. C.; Lusztyk, J.; Ingold, K. U. J. Am. Chem. Soc. 1984, 106, 1793. (b) Saebo, S.; Beckwith, A. L. J.; Radom, L. J. Am. Chem. Soc. 1984, 104, 5119.

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The β-(Phosphatoxy)alkyl Radical Rearrangement cyclopentadienyl and cyclopropenyl radicals, as revealed by EPR-spectroscopy,8,9 and of simple competition experiments showing the phosphatoxy migration to be several orders of magnitude faster than the acyloxy shift, led us to suggest that this polarization is general to both the 3- and 5-center shifts.2a We have now determined the migration rate constants of a series of p-substituted diphenyl phosphate esters and find that they fit to a simple correlation with the Hammett σp-parameter providing strong support for polarization of the transition states for migration as indicated in Figures 1 and 2.

J. Am. Chem. Soc., Vol. 118, No. 28, 1996 6667 Chart 1

Results and Discussion Competition experiments in this laboratory in which 3 was allowed to react with tributyltin hydride under AIBN initiation in benzene at reflux revealed the diphenylphosphatoxy group to migrate stereospecifically to 4, and to the exclusion of the acetoxy group, indicating a difference in rate constant of at least two orders of magnitude. More quantitative experiments in the Giese laboratory put the rate constant for the rearrangement of radical 5 to 6 at 8 × 106 s-1,3a as opposed to 5.2 × 102 s-1 for that of the corresponding acetate (7 f 8).10 Combined with the earlier observation of Ingold on the effect of solvents on the rate of the acyloxy migration and the accelerating effect of electron-withdrawing substituents on the migrating ester in the same, these differences in rate constant strongly suggested a significant polar component to the transition states for the phosphatoxy migration. To test this hypothesis we set out to measure the rate constants for the rearrangement of a series of β-(phosphatoxy)alkyl migrations and to look for linear free energy relationships with either Hammett σ-parameters or, failing that, with the free radical equivalents as devised by several groups. The various substrates and authentic product samples were prepared either as previously described (9, 14, 19)2a or by reaction of the appropriate ethyl diaryl phosphite with iodine, to give the diaryl iodophosphate,11 followed by addition of styrene bromohydrin or 1-, or 2-phenylethanol (15-18, 2023). The diethyl phosphates (24-26) were also prepared in order to assess the rate of migration of a simple dialkyl phosphate group. The kinetics were conducted by the radical clock method12 using quenching of the unrearranged primary alkyl radicals by benzeneselenol as the metronomic standard.13 This particular clock reaction was introduced by Newcomb for the determination of picosecond radical kinetics14 but we have prefered to use our recent adaptation in which a fixed, catalytic amount of PhSeH introduced as PhSeSePh is constantly regenerated by slow addition of 1 molar equiv of tributyltin hydride as this avoids the preparation and handling of PhSeH (8) (a) Sutcliffe, R.; Lindsay, D. A.; Griller, D.; Walton, J. C.; Ingold, K. U. J. Am. Chem. Soc. 1982, 104, 4674. (b) Schreiner, K.; Berndt, A. Angew. Chem., Int. Ed. Engl. 1976, 15, 698. (9) (a) Barker, P. J.; Davies, A. G.; Tse, M.-W. J. Chem. Soc., Perkin Trans. 2 1980, 941. (b) Davies, A. G.; Lusztyk, E.; Lusztyk, J. J. Chem. Soc., Perkin Trans. 2 1982, 729. (c) Davies, A. G.; Goddard, J. P.; Lusztyk, E.; Lusztyk, J. J. Chem. Soc., Perkin Trans. 2 1982, 737. (d) Davies, A. G.; Lusztyk, E.; Lusztyk, J.; Marti, V. P. J.; Clark, R. J. H.; Stead, M. J. J. Chem. Soc., Perkin Trans. 2 1983, 669. (10) Korth, H.-G.; Sustmann, R.; Groninger, K. S.; Leisung, M.; Giese, B. J. Org. Chem. 1988, 53, 4364. (11) (a) Forsman, J. P.; Lipkin, D. J. Am. Chem. Soc. 1953, 75, 3145. (b) Stowell, J. K.; Widlanski, T. S. Tetrahedron Lett. 1995, 36, 1825. (12) (a) Ingold, K. U.; Griller, D. Acc. Chem. Res. 1980, 13, 317. (b) Newcomb, M. Tetrahedron 1993, 49, 1151. (13) In using this method, we make the reasonable assumption that the rate of the clock reaction is not significantly affected by the presence of the β-phosphatoxy group and its substituents. (14) (a) Newcomb, M.; Varick, T. R.; Ha, C.; Manek, M. B.; Yue, X. J. Am. Chem. Soc. 1992, 114, 8158. (b) Martin-Esker, A. A.; Johnson, C. C.; Horner, J. H.; Newcomb, M. J. Am. Chem. Soc. 1994, 116, 9174.

Table 1. Kinetic Data ratio of reduction to migration mol % [PhSeSePh] PhSeSePh (M × 103) 9, H 10, Me 11, OMe 12, Cl 13, CF3 4.0 5.0 6.0 8.0 10.0 12.0 14.0 16.0 18.0 24.0 32.0 40.0 50.0

0.39 0.49 0.59 0.78 0.98 1.17 1.37 1.56 1.76 2.37 3.16 3.95 4.94

1.94 1.43 1.57 2.57

1.76 2.51 3.90 4.78 5.33

3.17 3.71 4.46

2.23 3.12 3.95 4.62 5.54

0.54 0.63 0.75 0.85 0.97 1.14

0.32 0.43 0.55 0.63 0.87

Table 2. Kinetic Data for 24

a

mol % PhSeSePh

[PhSeSePh] (M × 105)

ratio red/miga

2.0 3.0 4.0 5.0 6.0

3.98 5.97 7.96 9.95 11.94

10.9 13.9 16.6 20.7 22.8

Ratio of reduction to migration.

and allows the reaction to be driven to completion while maintaining pseudo-first-order conditions.15 The ratios of reduction to migration products at each of the different concentrations of PhSeH (PhSeSePh) used are collected in Table 1 for substrates 9-13 and in Table 2 for 24. Plotting of the ratio of reduction to migration products against [PhSeH] gave, for each substrate, a straight line whose gradient is equal to kH/kR, where kH is the rate constant for the reduction of primary (15) Crich, D.; Jiao, X.-Y.; Yao, Q.; Harwood, J. S. J. Org. Chem. 1996, 61, 2368.

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6668 J. Am. Chem. Soc., Vol. 118, No. 28, 1996

Crich and Jiao Table 4. Determination of Arrhenius Parameters for 9 f 19 1000/T 2.83 3.04 3.19 3.57 4.03 4.33 a

temp (K) 353 329 313 280 248 231

[PhSeH] (M)

ratio kH 19/14 (M-1 s-1) 2.2 × 10 1.6 × 109 1.4 × 109 9.8 × 108 6.5 × 108 4.9 × 108 9

2.93 × 10-4 2.93 × 10-4 2.93 × 10-4 2.93 × 10-4 2.93 × 10-4

0.66 0.31 0.18 0.05 0.02

kR (s-1)

log(kR)

× 3.1 × 105 1.3 × 105 5.1 × 104 9.5 × 103 2.9 × 103

5.9 5.5 5.1 4.7 4.0 3.5

a8.0

105

Taken from Table 3 (in benzene).

Figure 3. Hammett plot i. Table 3. Rate and σ Constants psubs substituent 9 10 11 12 13 24 a

H Me OMe Cl CF3

slopea (×10-3) 2.41 ( 0.78 4.64 ( 1.28 3.64 ( 0.85 0.60 ( 0.10 0.17 ( 0.06 154 ( 24

logσ• kRa σp (s-1 × 10-6) (kR) (Hammett) (Arnold) 0.80 0.41 0.53 3.20 11.6 0.012

5.90 5.61 5.72 6.51 7.06

0.00 -0.14 -0.12 0.24 0.53

0.00 0.015 0.018 0.011 -0.009

Errors are at the 95% confidence interval (3.2σ).

alkyl radicals by PhSeH and kR is the rate constant for the rearrangement in question. Substitution of 1.9 × 109 M-1s-1, calculated at 80 °C from the Arrhenius function [log(kH) ) 10.4-1.8/2.3RT], for kH gave the rate constants kR in Table 3. It is immediately evident from inspection of Table 3 that the nature of the substituent R in the migrating group OP(dO)(OR)2 has a significant effect on the rate of the β-(phosphatoxy)alkyl radical migration. Thus, within the series of p-substituted diaryl phosphates (9-13) rate constants differ by a factor of as much as 29 (cf. 10 and 13). It is also apparent that even the slowest diaryl phosphate migration measured is some 30-fold more rapid than that of the diethyl phosphate 24. Within the series 9-13 log(kR) was found to vary in a linear fashion with the Hammett σp parameter16 (Table 3, Figure 3). On the other hand, no correlation whatsoever was found on plotting log(kR) against the EPR-derived, Arnold σ• parameter17 (Table 3) for the stabilization of benzyl radicals by para substituents or other radical σ-parameters, such as that of Jackson18 based on the decomposition of a series of dibenzylmercury compounds.19 The lack of correlation of log(kR) with σ• scales and the strong one with σp, leading to a reaction coefficient F of 2.1, indicates that the β-(phosphatoxy)alkyl radical migration occurs through highly polarized transition states in which significant negative charge resides on the phosphate moiety. We therefore believe that Figures 1 and 2 [X ) P(OR)2] are reasonable qualitative representations of the 5-center-5-electron and 3-center-3-electron (16) Taken from Exner, O. in Correlation Analysis in Chemistry; Chapman, N. B., Shorter, J., Eds.; Plenum Press: New York, 1978; Chapter 10. (17) (a) Dust, J. M.; Arnold, D. R. J. Am. Chem. Soc. 1983, 105, 6531. (b) Wayner, D. D. M.; Arnold, D. R. Can. J. Chem. 1984, 62, 1164. (18) (a) Dinc¸ tu¨rk, S.; Jackson, R. A.; Townson, M. J. Chem. Soc., Chem. Commun. 1979, 172. (b) Agirbas, H.; Jackson, R. A. J. Chem. Soc., Perkin Trans. 2 1983, 739. (19) (a) For a discussion of the pros and cons of the various σ• scales in the literature see: Jackson, R. A. In Substituent Effects in Radical Chemistry; Viehe, H. G., Janousek, Z., Mere´nyi, R., Eds.; Reidel Publishing: Dordrecht, 1986; p 325. (b) For recent work on σ• scales see: Jiang, X. K.; Ji, G. Z. J. Org. Chem. 1992, 57, 6052 and references cited therein.

Figure 4. Arrhenius plot i.

migrations, respectively. In the light of these conclusions, a related study with 27 in which the migrating ester is kept constant and a substituent (X) varied should reveal a correlation between the electron donating ability of X and the migration rate. Indeed, Beckwith and Duggan have carried out such a series of experiments for the acyloxy migration, including a detailed 17O-NMR analysis of the mechanism (1,2 vs 2,3) as a function of X, and do find the anticipated correlation.20 Of course, the polar transition states advanced here and represented in Figures 1 and 2 are only separated from tight radical cationanion pairs by a small margin. It is to be expected that this threshold will be crossed, and radical cation-anion pairs become true intermediates, as the ability of the two fragments to support charge increases and as the solvent polarity is augmented. In the extreme, as demonstrated by the work of Giese with the radical 28 in allyl alcohol as solvent,21 it should be possible to trap radical cation intermediates with external nucleophiles.

By conducting the rearrangement of 9 over an 120 °C range of temperature (Table 4, Figure 4) the Arrhenius parameters for the one example were determined to be log(kR) ) (10.2 ( 0.8) - (7.0 ( 1.0)/2.3RT.22 While this equation is certainly useful for predicting the rate constant for the migration at a given temperature, it must be emphasized that it describes the sum of the 3-center-3-electron and the 5-center-5-electron (20) Beckwith, A. L. J.; Duggan, P. J. Private communication. (21) Giese, B.; Beyrich-Graf, X.; Burger, J.; Kesselheim, C.; Senn, M.; Scha¨fer, T. Angew. Chem., Int. Ed. Engl. 1993, 32, 1742. (22) . Errors are at the 95% confidence interval (3.2σ).

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The β-(Phosphatoxy)alkyl Radical Rearrangement processes. As such we have preferred not to draw conclusions about the nature of either transition state from this hybrid equation. Finally, it is of some interest to reflect on the absolute magnitude of the rate constants presented in Table 3 in relation to those of prototypical radical rearrangements used in many synthetic schemes. Thus, although it is commonly acknowledged that β-ester functions do not compete effectively with the prototypical 5-hexenyl to cyclopentylmethyl (k ) 1.4 × 106 s-1 at 80 °C)23 or cyclopropylmethyl to homoallyl (3.7 × 108 s-1 at 80 °C)24 rearrangements, we see that a degree of caution is indicated when the ester is a diaryl phosphate, or we suspect a nitrate or sulfonate ester whose migration would yield a relatively stabilized radical. Experimental Section General Protocol for Preparation of 10-13, 15-18, 20-23. 2-Bromo-1-phenylethyl Bis(4′-methylphenyl) Phosphate (10). 4-Methylphenol (1.51 g, 14 mmol) in THF (20 mL) was added to a stirred suspension of sodium hydride (0.60 g, 60% in mineral oil, 15 mmol) in THF (10 mL) under Ar at 0 °C resulting, after 15 min, in a clear solution. A solution of ethyl dichloro phosphite (0.97 g, 6.6 mmol) in THF (20 mL) was then added dropwise and the reaction mixture subsequently stirred for 1.5 h at room temperature. The resulting solution was passed through a short silica gel column, eluting with ether, then concentrated under vacuum. Chromatography on silica gel (eluent: hexane/ethyl acetate 4/1) gave ethyl bis(4′-methylphenyl) phosphite (1.89 g, 99%) as a colorless oil. 1H-NMR δ 1.33 (3 H, t, J ) 7.1 Hz), 2.30 (6 H, s), 4.20 (2 H, q, J ) 7.1 Hz), 6.98 (2 H, d, J ) 8.0 Hz), 7.10 (2 H, d, J ) 8.4 Hz); 13C-NMR δ 16.7, 20.7, 58.5, 120.0 (d, J ) 7.6 Hz), 130.1, 133.1, 149.3 (d, J ) 3.6 Hz); 31P-NMR δ 129.82. Iodine (1.32 g, 5.2 mmol) was added to a stirred solution of the above prepared phosphite (1.50 g, 5.2 mmol) in dichloromethane (15 mL) at -30 °C under Ar. After 15 min the so-formed phosphorylating agent was added to a mixture of styrene bromohydrin (1.05 g, 5.20 mmol) and pyridine (1.63 g, 20.6 mmol) in dichloromethane (15 mL), stirred under Ar at -30 °C. The reaction mixture was then allowed to come to 0 °C and then diluted with dichloromethane (40 mL) and washed with saturated NH4Cl (20 mL), saturated Na2S2O3 (20 mL), and brine (20 mL). The organic layer was dried on MgSO4, concentrated, and purified by chromatography on silica gel (eluent: hexane/ethyl acetate 4/1) to give the title compound as a colorless oil. 1H-NMR δ 2.27 (3 H, s), 2.32 (3 H, s), 3.59 (1 H, ddd, J ) 2.1, 5.4, 10.9 Hz), 3.70 (1 H, dd, J ) 7.0, 10.9 Hz), 5.69 (1 H, dd, J ) 5.5, 7.0 Hz), 6.8-7.3 (13 H, m); 13C-NMR δ 20.66, 20.72, 34.7 (d, J ) 8.2 Hz), 80.5 (d, J ) 5.5 Hz), 119.7 (d, J ) 4.6 Hz), 119.9 (d, J ) 4.4 Hz), 123.0, 126.7, 129.1, 130.1, 134.7, 134.9, 136.8, 148.1 (d, J ) 6.5 Hz), 148.2 (d, J ) 6.5 Hz); 31P-NMR δ -11.7; IR ν 3037, 2963, 1507, 1454, 1289, 1193, 993, 708, 596 cm-1. Anal. Calcd for C22H22BrO4P: C, 57.28; H, 4.81. Found: C, 57.15; H, 4.76. 2-Bromo-1-phenylethyl Bis(4′-methoxyphenyl) Phosphate (11). 1H-NMR δ 3.59 (1 H, ddd, J ) 2.1, 5.4, 10.9 Hz), 3.70 (1H, dd, J ) 6.9, 11.0 Hz), 3.74 (3 H, s), 3.78 (3 H, s), 5.67 (1 H, dt, J ) 5.4, 7.1 Hz), 6.8-7.4 (13 H, m); 13C-NMR δ 34.8 (d, J ) 8.5 Hz), 55.55, 55.60, 80.5 (d, J ) 3.4 Hz), 114.5, 114.6, 120.9 (d, J ) 4.4 Hz), 121.1 (d, J ) 4.5 Hz), 126.7, 128.6, 129.2, 136.9 (d, J ) 3.2 Hz), 143.9 (d, J ) 7.7 Hz), 144.0 (d, J ) 7.6 Hz); 31P-NMR δ -11.08; IR ν 3065, 2958, 1594, 1456, 1289, 1178, 1031, 700, 597 cm-1. Anal. Calcd for C22H22BrO6P: C, 53.56; H, 4.50. Found: C, 53.14; H, 4.41. 2-Bromo-1-phenylethyl Bis(4′-chlorophenyl) Phosphate (12). 1HNMR δ 3.58 (1 H, ddd, J ) 2.8, 4.7, 11.1 Hz), 3.71 (1 H, dd, J ) 7.8, 11.1 Hz), 5.7 (1 H, dd, J ) 4.8, 7.8 Hz), 6.8-7.4 (13 H, m); 13C-NMR δ 34.5 (d, J ) 8.9 Hz), 81.4 (d, J ) 5.2 Hz), 121.3 (d, J ) 4.7 Hz), 121.6 (d, J ) 4.6 Hz), 126.7, 128.8, 129.5, 129.6, 129.8, 130.8, 131.0, 136.5, 148.5 (d, J ) 7.6 Hz), 148.8 (d, J ) 7.6 Hz); 31P-NMR δ -12.2; IR ν 3093, 3066, 2966, 1588, 1487, 1287, 1196, 998, 700, 647, 595 (23) Chatgilialoglu, C.; Ingold, K. U.; Scaiano, J. C. J. Am. Chem. Soc. 1981, 103, 7739. (24) Bowry, V. W.; Lusztyk, J.; Ingold, K. U. J. Am. Chem. Soc. 1991, 113, 5687.

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J. Am. Chem. Soc., Vol. 118, No. 28, 1996 6669 cm-1. Anal. Calcd for C20H16BrCl2O4P: C, 47.84; H, 3.21. Found: C, 47.65; H, 3.28. 2-Bromo-1-phenylethyl Bis(4′-(trifluoromethyl)phenyl) Phosphate (13). 1H-NMR δ 3.60 (1 H, ddd, J ) 3.2, 4.4, 11.2 Hz), 3.73 (1 H, dd, J ) 8.3, 11.2 Hz), 5.71 (1 H, dt, J ) 4.4, 8.1 Hz), 7.0-7.7 (13 H, m); 13C-NMR δ 34.3 (d, J ) 9.5 Hz), 82.0 (d, J ) 5.5 Hz), 120.3 (d, J ) 5.1 Hz), 120.6 (d, J ) 5.1 Hz), 123.7 (dq, J ) 4.4, 271.9 Hz), 126.6, 127.1, 127.2, 128.9, 129.7, 136.3, 152.3 (d, J ) 6.5 Hz), 152.6 (d, J ) 6.5 Hz); 31P-NMR δ -12.85; IR ν 3070, 2970, 1512, 1326, 1127, 1068, 700, 594 cm-1. Anal. Calcd for C22H16BrF6O4P: C, 46.42; H, 2.83. Found: C, 46.40; H, 2.79. 2-Bromo-1-phenylethyl Diethyl Phosphate (24). Iodine (0.83 g, 3.3 mmol) was added to a solution of triethyl phosphite (0.56 g, 3.58 mmol) in dichloromethane (2 mL) at 0 °C under Ar. After 5 min the clear, colorless solution was allowed to warm to room temperature and then added dropwise over 5 min to a solution of styrene bromohydrin (0.60 g, 3.0 mmol) and pyridine (0.94 g, 12 mmol) in dichloromethane (5 mL) at room temperature. After being stirred for 10 min, the reaction mixture was diluted with ether (50 mL), washed with 25% NaHSO4 (3 × 5 mL) and 10% sodium hydrogen phosphate buffer (pH 7, 5 mL), dried (MgSO4), and concentrated under vacuum. Column chromatography (eluent: hexane/ethyl acetate 3/1) afforded the title compound (0.42 g, 41%) as a colorless oil. 1H-NMR δ 1.12 (3 H, dt, J ) 1.0, 7.1 Hz), 1.26 (3 H, dt, J ) 1.0, 7.1 Hz), 3.59 (1 H, ddd, J ) 2.2, 4.9, 10.9 Hz), 3.69 (1 H, dd, J ) 7.4, 10.9 Hz), 3.88 (2 H, dq, J ) 3.0, 7.2 Hz), 4.09 (2 H, ddq, J ) 7.2, 10.1, 16.0 Hz), 5.47 (1 H, dt, J ) 5.0, 7.6 Hz), 7.3-7.3 (5 H, m); 13C-NMR δ 15.8 (d, J ) 9.4 Hz), 15.9 (d, J ) 9.9 Hz), 35.3 (d, J ) 8.0 Hz), 63.7 (d, J ) 5.8 Hz), 64.0 (d, J ) 5.5 Hz), 78.9 (d, J ) 4.9 Hz), 126.5, 128.5, 129.0, 137.6; 31P-NMR δ -1.73; IR ν 3033, 2978, 1455, 1272, 1031, 986, 797, 701, 590 cm-1. Anal. Calcd for C12H18BrO4P: C, 42.75; H, 5.38. Found: C, 42.81; H, 5.36. 1-Phenylethyl Bis(4′-methylphenyl) Phosphate (15). This secondary benzylic phosphate was stable to the neutral migration conditions (Bu3SnH, benzene, 80 °C) and also to the standard conditions for preparation of an authentic sample; unfortunately any attempt at purification by silica gel chromatography with a variety of neutral and basified solvents led to decomposition. The essential spectral characteristics are therefore taken from a crude preparation of an authenic sample. 1H-NMR δ 1.63 (3 H, dd, J ) 1.0, 6.5 Hz), 2.28 (3 H, s), 2.31 (3 H, s), 5.68 (1 H, quint, J ) 6.6 Hz), 6.89-7.34 (13 H, m). 1-Phenylethyl Bis(4′-methoxyphenyl) Phosphate (16). This secondary benzylic phosphate was stable to the neutral migration conditions (Bu3SnH, benzene, 80 °C) and also to the standard conditions for preparation of an authentic sample; unfortunately any attempt at purification by silica gel chromatography with a variety of neutral and basified solvents led to decomposition. The essential spectral characteristics are therefore taken from a crude preparation of an authenic sample. 1H-NMR δ 1.63 (3 H, d, J ) 6.7 Hz), 3.76 (3 H, s), 3.78 (3 H, s), 5.67 (1 H, quint, J ) 6.6 Hz), 6.71-7.36 (13 H, m). 1-Phenylethyl Bis(4′-chlorophenyl) Phosphate (17). This secondary benzylic phosphate was stable to the neutral migration conditions (Bu3SnH, benzene, 80 °C) and also to the standard conditions for preparation of an authentic sample; unfortunately any attempt at purification by silica gel chromatography with a variety of neutral and basified solvents led to decomposition. The essential spectral characteristics are therefore taken from a crude preparation of an authenic sample. 1H-NMR δ 1.65 (3 H, dd, J ) 1.0, 6.5 Hz), 5.67 (1 H, quint, J ) 6.9 Hz), 6.70-7.35 (13 H, m). 1-Phenylethyl Bis(4′-trifluoromethylphenyl) Phosphate (18). This secondary benzylic phosphate was stable to the neutral migration conditions (Bu3SnH, benzene, 80 °C) and also to the standard conditions for preparation of an authentic sample; unfortunately any attempt at purification by silica gel chromatography with a variety of neutral and basified solvents led to decomposition. The essential spectral characteristics are therefore taken from a crude preparation of an authenic sample. 1H-NMR δ 1.68 (3 H, dd, J ) 1.0, 6.5 Hz), 5.72 (1 H, quint, J ) 6.8 Hz), 7.07-7.62 (13 H, m). 2-Phenylethyl Bis(4′-methylphenyl) Phosphate (20). 1H-NMR δ 2.31 (6 H, s), 3.00 (2 H, t, J ) 7.1 Hz), 4.41 (2 H, q, J ) 7.1 Hz), 7.01-7.31 (13 H, m); 13C-NMR δ 20.7, 36.6 (d, J ) 7.6 Hz), 69.3 (d, J ) 6.5 Hz), 119.7 (d, J ) 4.7 Hz), 126.7, 128.5, 129.0, 130.1, 134.8,

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6670 J. Am. Chem. Soc., Vol. 118, No. 28, 1996 136.7, 148.3 (d, J ) 7.6 Hz); 31P-NMR δ -10.91; IR ν 3031, 2959, 1507, 1455, 1293, 1193, 1056, 749 cm-1. Anal. Calcd for C22H23O4P: C, 69.10; H, 6.06. Found: C, 69.01; H, 6.09. 2-Phenylethyl Bis(4′-methoxyphenyl) Phosphate (21). 1H-NMR δ 3.00 (2 H, t, J ) 7.0 Hz), 3.78 (6 H, s), 4.41 (2 H, q, J ) 7.1 Hz), 6.78-7.30 (13 H, m); 13C-NMR δ 36.6 (d, J ) 6.5 Hz), 55.6, 69.3 (d, J ) 6.5 Hz), 114.6, 120.9 (d, J ) 4.5 Hz), 126.8, 128.5, 129.0, 136.8, 144.1 (d, J ) 7.6 Hz), 156.8; 31P-NMR δ -10.30; IR ν 3003, 2959, 1503, 1465, 1292, 1189, 1073, 833 cm-1. Anal. Calcd for C22H23O6P: C, 63.76; H, 5.59. Found: C, 63.29; H, 5.63. 2-Phenylethyl Bis(4′-chlorophenyl) Phosphate (22). 1H-NMR δ 3.01 92 H, t, J ) 6.8 Hz), 4.44 (2 H, q, J ) 6.9 Hz), 7.0-7.3 (13 H, m); 13C-NMR δ 36.5 (d, J ) 7.1 Hz), 69.7 (d, J ) 6.4 Hz), 121.6 (d, J ) 4.8 Hz), 126.7, 128.6, 129.0, 129.8, 130.8, 136.4, 148.8 (d, J ) 6.5 Hz); 31P-NMR δ -11.56; IR ν 3092, 2958, 1588, 1484, 1304, 1197, 1057, 782 cm-1. Anal. Calcd for C20H17Cl2O4P: C, 56.75; H, 4.05. Found: C, 56.50; H, 4.14. 2-Phenylethyl Bis(4′-(trifluoromethyl)phenyl) Phosphate (23). 1 H-NMR δ 3.04 (2 H, t, J ) 6.7 Hz), 4.50 (2 H, q, J ) 6.7 Hz), 7.27.6 (13 H, m); 13C-NMR δ 36.5 (d, J ) 7.3 Hz), 70.1 (d, J ) 6.3 Hz), 120.3 (d, J ) 5.1 Hz), 123.7 (q, J ) 272.5 Hz), 127.0, 127.26, 127.30, 128.6, 129.0, 136.3, 152.6 (d, J ) 7.4 Hz); 31P-NMR δ -12.32; IR ν 3068, 2965, 1498, 1299, 1169, 1068, 847, 799 cm-1. Anal. Calcd for C22H17F6O4P: C, 53.89; H, 3.49. Found: C, 53.96, H, 3.50. 1-Phenylethyl Diethyl Phosphate (25).25 This compound was prepared analogously to 24. 1H-NMR δ 1.18 (3 H, dt, J ) 1.0, 7.1 Hz), 1.28 (3 H, dt, J ) 1.0, 7.1 Hz), 1.63 (3 H, d, J ) 6.5 Hz), 3.92 (2 H, dq, J ) 0.6, 7.1 Hz), 4.05 (2 H, m), 5.47 (1 H, dq, J ) 6.6, 7.1 Hz), 7.27-7.40 (5 H, m); 13C-NMR δ 15.9 (d, J ) 6.5 Hz), 16.0 (d, J ) 6.5 Hz), 24.2 (d, J ) 5.5 Hz), 63.5 (2C, d, J ) 5.5 Hz), 76.6 (d, J ) 5.5 Hz), 125.9, 128.1, 128.4, 141.7 (d, J ) 5.5 Hz); 31P-NMR δ -1.12. 2-Phenylethyl Diethyl Phosphate (26).26 This compound was prepared analogously to 24. 1H-NMR δ 1.28 (6 H, dt, J ) 1.3, 7.1 Hz), 2.99 (2 H, t, J ) 7.0 Hz), 4.02 (4 H, dq, J ) 1.1, 7.1 Hz), 4.23 (2 H, q, J ) 7.1 Hz), 7.20-7.33 (5 H, m); 13C-NMR δ 15.9 (d, J ) 6.6 Hz), 36.6 (d, J ) 6.9 Hz), 63.5 (d, J ) 5.7 Hz), 67.7 (d, J ) 6.0 Hz), 126.5, 128.3, 137.0; 31P-NMR δ -0.49. Kinetics of Rearrangement of 9. General Method for Determination of Rearrangement Kinetics. A stock solution of 9 (0.866 g) in benzene (40 mL) was prepared and 4 mL (0.2 mmol) transferred to each of seven 50-mL round-bottomed Pyrex flasks. A stock solution of PhSeSePh (0.05 g) made up to 25 mL in benzene was then used to add 5, 6, 8, 12, 14, 16, or 18 mol % of PhSeSePh to these flasks. An amount of Bu3SnH corresponding to that of PhSeSePh was added to each flask and the volume made up to 20 mL with benzene. A steady stream of Ar was then passed through each flask for several minutes. Each flask was brought to reflux, with stirring under Ar, while Bu3(25) Hammerschmidt, F.; Vo¨llenkle, H. Liebigs Ann. 1986, 2053. (26) Jung, A.; Engel, R. J. Org. Chem. 1975, 40, 3652.

Crich and Jiao SnH (0.070 g) and AIBN (1.6 mg) in benzene (1 mL) was added dropwise with a motor-driven syringe pump over 2.3 h. Reflux was continued for a further 1 h before the solvent was removed in Vacuo and the residue examined by 1H-NMR. In each case the substrate was completely consumed. Integration of the H-1 resonance in 14 and the H-2 resonance in 19 gave the ratio of (reduction/migration) 14/19 as recorded in Table 1. The spectral data for 14 and 19 were identical to those recorded in the literature.2a The total volume change in the course of the reaction, owing to the addition of Bu3SnH, was essentially negligable at 5%. In calculating the molar concentration of PhSeSePh and also of PhSeH a mean volume of 20.5 mL was taken. Kinetics of Rearrangement of 24. Five flasks were made up, using stock solutions, containing 24 (33.71 mg, 0.1 mmol), PhSeSePh (2, 3, 4, 5, or 6 mol %), and Bu3SnH (2, 3, 4, 5, or 6 mol %) in benzene (50 mL). A steady stream of Ar was then passed through each flask for several minutes. Each flask was then brought to reflux, with stirring under Ar, while Bu3SnH (0.035 g) and AIBN (0.8 mg) in benzene (0.5 mL) was added dropwise with a motor-driven syringe pump over 2.3 h. Reflux was continued for a further 1 h before the solvent was removed in Vacuo and the residue examined by 1H-NMR. In each case the substrate was completely consumed. Integration of the H-1 resonance in 25 and the H-2 resonance in 26 gave the ratio of (reduction/ migration) 25/26 as recorded in Table 2. The total volume change in the course of the reaction, owing to the addition of Bu3SnH, was essentially negligible at 1%. Determination of the Arrhenius Function for Rearrangement of 9. A stock solution of 9 (0.8664 g) in toluene (40 mL) was prepared and 4 mL (0.2 mmol) transferred to each of five 50-mL round-bottomed flasks. A stock solution of PhSeSePh (0.05 g) in toluene (50 mL) was made up and 1.87 mL (0.006 mmol) added to each flask, followed by Bu3SnH (2.1 mL of a 0.003 M solution in toluene, 0.0072 mmol). Each flask was then made up to 20 mL with toluene and purged with a steady stream of Ar for several minutes. In turn, each flask was equilibrated at the required temperature (Table 4) and irradiated with a 100-W medium-pressure Hg lamp (through Pyrex) while Bu3SnH and AIBN in toluene (1 mL of a stock solution containing 0.700 g, 2.41 mmol of Bu3SnH and 0.0164 g, 0.1 mmol of AIBN in a total of 10 mL) was added with the syringe pump over 2.3 h. After the addition the irradiation was continued for a further 1 h before the solvent was removed under vacuum and the residue examined by 1H-NMR to give the data recorded in Table 4. The data for 80 °C were taken from Table 1.

Acknowledgment. We thank A. L. J. Beckwith and P. J. Duggan, ANU, for stimulating discussion and for prior disclosure of their related work, W. L. Mock, UIC, for helpful suggestions, and the NIH (CA 60500) for support of this work. D.C. is a Fellow of the A. P. Sloan Foundation. JA961275A